Evidence-based medicine, statistics and pharmacy practice

Adam La Caze

PHRM1102 W7 Workshop

Learning outcomes (Module)

  1. Apply skills in evidence-based practice to addressing therapeutic questions [Pharmacy]
  2. Evaluate the strengths and weaknesses of key pharmacy resources for addressing therapeutic questions [Pharmacy]
  3. Be able to interpret and explain common measures of effect from clinical studies [Pharmacy]
  4. Be able to describe (in general terms) the logic of statistical inference (including key concepts: p values, confidence intervals, power, type I and type II errors) [Statistics]
  5. Be able to identify different data types, common summary measures and and how they a represented [Statistics]
  6. Be able to describe key types of statistical tests [Statistics]
  7. Be able to read health research (specifically randomized trials of pharmaceuticals) and identify the primary statistical hypothesis, PICO, the study type, the measure of effect (ratio, difference; relative, absolute) and the meaning of the statistical result [Pharmacy + Statistics]

Learning outcomes (W7)

  1. Applying skills in evidence-based practice to addressing therapeutic questions
  2. Evaluating the strengths and weaknesses of key pharmacy resources for addressing therapeutic questions
  3. Interpreting and explaining common measures of effect from clinical studies, and
  4. Reading health research and identify the primary statistical hypothesis, PICO, the study type, the measure of effect (ratio, difference; relative, absolute) and the meaning of the statistical result

Engagement tasks

Sonia would like to know whether a non-steroidal anti-inflammatory drug, such as ibuprofen or diclofenac, would be more effective for her knee pain compared to paracetamol.

In PICO form:

PICO Details
Participants People with knee osteoarthritis
Intervention Non-steroidal antiinflammatory drugs
Comparator Paracetamol
Outcome Pain self-report and/or assessments of functional ability in osteoarthritis

Arrange the names of your group into alphabetical order.

  • The first two students need to search Pubmed for randomized trials that answer the question

  • The second two students need to search Pubmed for systematic reviews that answer the question

  • The third two students need to use either DynaMed or UptoDate to answer the question

  • If your group is larger than 6, any remaining students can take their pick from the options above

Questions?

  • Sonia’s knee pain
  • Subgroup effects
  • Cholinesterase inhibitors in dementia
  • External validity
  • Limits of randomized trials

Addressing therapeutic questions

Which was the first treatment to show mortality benefit in Covid-19?

How was this demonstrated?

Molnupiravir

You look after a residential aged care facility. They have just notified that they will receive a shipment of a Covid-19 antiviral, molnupiravir.

They ask you

  • How does molnupiravir work? How is it given?
  • When is the drug recommended? (What are the criteria for use?)
  • What is the evidence that it improves outcomes?

Key resources

Evaluating evidence

What are some of the challenges of demonstrating drug harms?

Selective Cox-2 inhibitors

  • Selective Cox-2 inhibitors were developed in the late 1990’s to provide an alternative to NSAIDs that was hoped to cause less gastrointestinal ulcers
  • Rofecoxib and celecoxib are two early COXIBs
  • Two key studies showing that rofecoxib and celecoxib cause less gastrointestinal ulcers are VIGOR and CLASS, respectively

VIGOR (Bombardier et al., 2000)

Participants Patients with rheumatoid arthritis who were expected to require NSAIDs for at least a year
Intervention Rofecoxib 50 mg once daily
Comparator Naproxen 500 mg twice daily
Outcome Confirmed clinical upper gastrointestinal event

During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95% confidence interval 0.3 to 0.6; P < 0.001).

The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups.

APPROVe (Bresalier et al., 2005)

Participants Patients with a history of colorectal adenomas
Intervention Rofecoxib 25 mg daily
Comparator Placebo
Outcome Recurrent neoplastic polyps of the large bowel

A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008).

CLASS (as reported)(Silverstein et al., 2000)

Participants Patients with rheumatoid arthritis or osteoarthritis and expected to need continuous treatment with a NSAID
Intervention Celecoxib 400 mg twice a day
Comparator Ibuprofen 800 mg three times a day or diclofenac 75 mg twice a day
Outcome Symptomatic upper GI ulcers or ulcer complications

For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P = .09) and 2.08% vs 3.54% (P= .02), respectively.

CLASS (reality)

  • Juni et al. (2002) highlights that the original protocols were for two studies, one comparing celecoxib with diclofenac and the other with ibuprofen.

  • The original protocol describes the studies continuing for 12 and 15 months respectively, and uses a more stringent FDA-specified criteria for judging ulcer-related complications.

  • When the data is analysed as planned there is no difference between celecoxib, ibuprofen and diclofenac

PICO and measures of effect

MOVe-OUT (Jayk Bernal et al., 2022)

Task

  1. Provide the study PICO

  2. If relevant, calculate the RR, RRR, ARR and NNT

PICO

Participants Nonhospitalised, unvaccinated adults with mild-to-moderate lab-confirmed Covid-19 and at least one risk factor for severe illness of less than 5 days
Intervention Molnupiravir 800 mg twice daily for 5 days
Comparator Placebo
Outcome Incidence of hospitalisation or death at day 29

In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% CI, −5.9 to −0.1).

Measures of effect

2 x 2 table
Endpoint No endpoint Total
Treatment 48 661 709
Control 68 631 699
  • The relative risk of hospitalisation or death in participants who received molnupiravir compared to placebo is 70%
  • The absolute risk reduction of hospitalisation or death in participants who received molnupiravir compared to placebo is 2.96%
  • The number needed to treat to prevent one case of hospitalisation or death is 34

External validity

Comment on the relevance of these findings for residents in a aged care facility.

References

Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargos, R., Davis, B., & al, et. (2000). Comparision of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR study group. New England Journal of Medicine, 343, 1520–1528.

Bresalier, R. S., Sandler, R. S., Quan, H., Bolognese, J. A., Oxenius, B., Horgan, K., Lines, C., Riddell, R., Morton, D., Lanas, A., Konstam, M. A., & Baron, J. A. (2005). Cardiovascular events associated with Rofecoxib in a colorectal andenoma chemoprevention trial. New England Journal of Medicine, 352(11), 1092–1102.

Jayk Bernal, A., Gomes da Silva, M. M., Musungaie, D. B., Kovalchuk, E., Gonzalez, A., Delos Reyes, V., Martín-Quirós, A., Caraco, Y., Williams-Diaz, A., Brown, M. L., Du, J., Pedley, A., Assaid, C., Strizki, J., Grobler, J. A., Shamsuddin, H. H., Tipping, R., Wan, H., Paschke, A., … De Anda, C. (2022). Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. New England Journal of Medicine, 386(6), 509–520. https://doi.org/10.1056/NEJMoa2116044

Juni, P., Rutjes, A. W. S., & Dieppe, P. A. (2002). Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ (Clinical Research Ed), 324(7349), 1287–1288. http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=12039807&retmode=ref&cmd=prlinks

Silverstein, F. E., Gaich, G., Goldstein, J. L., Simon, L. S., Pincus, T., Whelton, A., Makuch, R., Eisen, G., Agrawal, N. M., Stenson, W. F., Burr, A. M., Zhao, W. W., Kent, J. D., Lefkowith, B., Verburg, K. M., & Geis, G. S. (2000). Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: The CLASS study: A Randomzed Controlled Trial. JAMA: The Journal of the American Medical Association, 284(1247-55).